Design,synthesis, docking and mechanistic studies of new thiazolyl/thiazolidinylpyrimidine-2,4-dione antiproliferative agents |
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Institution: | 1. Chemistry Department, Faculty of Science, Minia University, 61519 El-Minia, Egypt;2. Chemistry Department, College of Sciences and Humanities, Prince Sattam Bin Abdulaziz University, Al-Kharij, Saudi Arabia;3. Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf, Saudi Arabia;4. Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, 71526 Assiut, Egypt;5. Institute of Organic Chemistry, Karlsruher Institut fur Technologie, 76131 Karlsruhe, Germany;6. Institute of Biological and Chemical Systems (IBCS-FMS), Karlsruhe Institute of Technology, 76344 Eggenstein Leopoldshafen, Germany;7. Computational Chemistry Laboratory, Chemistry Department, Faculty of Science, Minia University, Minia 61519, Egypt |
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Abstract: | In this article, we display on the synthesis and biological evaluation of a new series of thiazolylpyrimidine 3a-l and thiazolidinylpyrimidine derivatives 5a-e. The structures of the new compounds were confirmed by using different spectral techniques including NMR, IR, mass spectroscopy in addition to elemental analyses. The cell viability of the new compounds was assessed against normal human mammary gland epithelial (MCF-10A) cell line. Data revealed that none of the compounds examined exhibited cytotoxic effects, and the cell viability for the compounds examined at 50 µM was greater than 87%. The antiproliferative activity of 3a-l and 5a-e was evaluated against four human cancer cell lines where the compounds showed promising activity. The most potent derivatives were compounds 3a, 3c, 3f, 3i, and 5b with GI50 values ranging from 0.90 µM to 1.70 µM against the four cancer cell lines in comparison to doxorubicin (GI50 = 1.10 µM). Compounds 3a, 3c and 3i showed potent antiproliferative activity with dual inhibitory action against EGFR and BRAFV600E. Compounds 3a, 3c, and 3i demonstrated promising AutoDock scores towards EGFR and BRAFV600E with values of ? 9.1 and ? 8.6, ?9.0 and ? 8.5, and ? 8.4 and ? 8.0 kcal/mol, respectively. The physicochemical and pharmacokinetic characteristics of 3a, 3c, and 3i were anticipated, demonstrating their oral bioavailability. |
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Keywords: | Uracil Thiazoles Thiazolidines Antiproliferative Kinases Docking MTT"} {"#name":"keyword" "$":{"id":"k0045"} "$$":[{"#name":"text" "$$":[{"#name":"__text__" "_":"3-(4 5-Dimethylthiazol-2-yl)-2 5-diphenyl-2"} {"#name":"italic" "_":"H"} {"#name":"__text__" "_":"-tetrazolium bromide ADMET"} {"#name":"keyword" "$":{"id":"k0055"} "$$":[{"#name":"text" "_":"Absorption distribution metabolism excretion and toxicity EGFR-TK inhibitors"} {"#name":"keyword" "$":{"id":"k0065"} "$$":[{"#name":"text" "_":"Epidermal growth factor receptor kinase inhibitors |
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